Journal of Alzheimer's Disease - Volume 37, issue 3

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ISSN 1387-2877 (P)

ISSN 1875-8908 (E)

Impact Factor 2018: 3.476

The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.

The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.

Abstract: Alzheimer's disease is multifactorial and involves several different mechanisms. The sporadic form of the disease accounts for over 99% of the cases. As of yet, there is no practical and widely available animal model of the sporadic form of the disease. In the Alzheimer's disease brain, the lysosomal enzyme asparaginyl endopeptidase is activated and translocated from the neuronal lysosomes to the cytoplasm, probably due to brain acidosis caused by ischemic changes associated with age-associated microinfarcts. The activated asparaginyl endopeptidase cleaves inhibitor-2 of protein phosphatase-2A, I2 PP2A , into I2NTF and I2CTF which translocate to the neuronal cytoplasm and…inhibit the protein phosphatase activity and consequently the abnormal hyperphosphorylation of tau. Employing adeno-associated virus serotype 1 (AAV1) vector containing I2NTF-CTF and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I2NTF-CTF rats show neurodegeneration and cognitive impairment at 4 months and abnormal hyperphosphorylation and aggregation of tau and intraneuronal accumulation of amyloid-β at 13 months. The AAV1-I2NTF-CTF rats not only offer a disease-relevant model of the sporadic form of Alzheimer's disease but also represent a practical and widely available animal model. This short perspective on the need to focus on and develop the disease-relevant models of the sporadic form of Alzheimer's disease very much reflects the thinking of Inge Grundke-Iqbal who passed away on September 22, 2012 and to whom this article is dedicated.
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Abstract: Alzheimer's disease (AD) is a multifactorial disorder that involves several different mechanisms. Over 99% of AD patients suffer from the sporadic form of the disease. Based on cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42 , total tau, and ubiquitin—the markers associated with the histopathological hallmarks of the disease (Aβ plaques and abnormally hyperphosphorylated neurofibrillary tangles)—previous studies identified five subgroups of AD. Here we report the potential diagnostic predictive value of hallucination, hypokinesia, paranoia, rigidity, and tremors in aged individuals for AD and differences in the prevalence of these symptoms in the CSF marker-based subgroups of the disease. Analysis of 196…clinically diagnosed AD or Alzheimer with Lewy body, and 75 non-AD neurological and non-neurological control cases, all from a single center, showed that the presence of hallucination, hypokinesia, paranoia, rigidity, or tremors individually, or the presence of any of these, could diagnose AD with sensitivities and specificities of 14% and 99%; 30% and 99%; 15% and 99%; 16% and 100%; 16% and 96%; and 47% and 92%, respectively. The pattern of the prevalence of the above symptoms varied from AD subgroup to subgroup. Presence of any of these symptoms, as well as presence of each individual symptom except tremors, significantly differentiated AD subgroups from the predominantly control cluster. These findings encourage the exploration of hallucination, hypokinesia, paranoia, rigidity, and tremors in identifying various subgroups of AD for stratification of patients for clinical trials to develop therapeutic drugs. This study is for the special issue of the Journal of Alzheimer's Disease honoring Inge Grundke-Iqbal who made several seminal contributions in AD research.
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Abstract: This review is dedicated to Inge Grundke-Iqbal who laid the foundations of the tau field, by isolating tau from the Alzheimer's disease (AD) brain, discovering that tau is hyperphosphorylated, and proving a critical role of protein phosphatase 2A (PP2A) and its endogenous inhibitor I2 PP2A in this process. This memorial starts with a few personal notes, and then covers how subcellular fractionation helped in isolating tau. We review in detail the role of PP2A and its endogenous inhibitor in tau phosphorylation. We discuss the role that methylation and phosphorylation have in regulating PP2A activity. We add what we have…contributed to understanding the role of tau and PP2A in AD using PP2A transgenic and knockout models, and conclude by addressing two underexplored areas in tau research: tau's non-canonical functions and the role distinct tau isoforms have in a physiological context.
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Abstract: Recent evidence implicated aberrant mammalian target of rapamycin (mTOR)-dependent signaling in both Alzheimer's disease (AD) and brain tumors. This review focuses on the potential mechanisms shared by both neurodegeneration and carcinogenesis. In particular, attention was paid to the possible roles of mTOR-dependent signaling in these two fundamental pathophysiological processes. We hypothesize that common stresses could lead either to progressive degeneration or uncontrolled carcinogenesis via cell type specific upregulation of mTOR-dependent signaling in the central nervous system while mTOR-mediated carcinogenesis might permit glial cells to escape from degeneration.

Abstract: Inge Grundke-Iqbal and Khalid Iqbal found a connection between microtubule associated tau and Alzheimer's disease. They described that abnormally phosphorylated tau is a component of the paired helical filaments found in the disease. Afterwards they described that tau hyperphosphorylation prevents microtubule assembly. Now trying to complement the relationship between microtubules and tau phosphorylation, we have commented on the effect of microtubule disassembly on tau phosphorylation. In this study, we investigated the role of microtubule depolymerization induced by nocodazole on tau phosphorylation in human neuroblastoma SH-SY5Y cells. Our results indicate that nocodazole provokes tau phosphorylation mediated by GSK3, as determined by…using AT-8 or Tau-1 antibodies. Interestingly, total GSK3β and GSK3β phosphorylation on Ser-9 are not altered during nocodazole treatment. In addition, microtubule stabilization with taxol had similar effects, likely because taxol and tau compete for the same binding sites on microtubules, and in the presence of taxol, tau could be detached from microtubules. Thus, unbound tau from microtubles can be phosphorylated by GSK3, even if the activity of GSK3 is not altered, probably because tau unbound to microtubules could be a better substrate for the kinase than microtubule-associated tau. These findings suggest that microtubule depolymerization can be a primary event in neurodegenerative disorders like Alzheimer's disease and that tau phosphorylation takes place afterwards.
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Abstract: Cholinergic dysfunction plays a crucial role in the memory deterioration of Alzheimer's disease, but the molecular mechanism is not fully understood. By employing a widely recognized cholinergic dysfunction rat model that was produced by intraperitoneal injection of scopolamine, we investigated the mechanisms underlying scopolamine-induced memory deficits. We found that scopolamine caused spatial learning and memory deficits that involved activation of glycogen synthase kinase-3β (GSK-3β) and impairments of dendrite arborization and spine formation/maturation associated with alterations of AMPAR, Homer1, and CREB. Pretreatment by intraperitoneal injection of lithium, an inhibitor of GSK-3, for one week prevented the synaptic changes and the learning…and memory deficits induced by scopolamine. Lithium treatment also activated cholineacetyltransferase and inhibited acetylcholinesterase, which might have also contributed to the improved memory. Our findings suggest that GSK-3β may be a key molecular mediator of cholinergic synaptic dysfunction, and that inhibition of GSK-3β by lithium may be promising in protecting cholinergic synaptic functions.
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Abstract: Microtubule-associated protein tau is found to be accumulated and aggregated in the brains of individuals with Alzheimer's disease and related tauopathies. Dual-specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk1A) is overexpressed in Down syndrome and may play a critical role in the early onset of tau pathology in this disease. To investigate the effect of Dyrk1A on tau expression, we co-expressed different isoforms of tau with Dyrk1A in HEK-293FT cells and measured the mRNA and protein levels of tau using RT-PCR and Western blots, respectively. We further investigated the mechanism of regulation of tau expression by Dyrk1A. We found that Dyrk1A enhanced…tau expression in a dose-dependent manner. The enhancement did not require the kinase activity of Dyrk1A. Dyrk1A increased the expression of tau isoforms containing exon 10 to a larger extent than isoforms lacking exon 10. The expression of endogenous tau in neuronal cells was also regulated by Dyrk1A, and increased tau levels were found in the brains of Ts65Dn mice that overexpress Dyrk1A due to partial trisomy of chromosome 16. Dyrk1A did not enhance tau gene transcription, but increased tau mRNA stability. These results suggest that Dyrk1A enhances tau expression by stabilizing its mRNA and provides a novel insight into the regulation of tau expression and a molecular mechanism of tauopathies.
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Abstract: A key characteristic of Alzheimer's disease and other tauopathies is the progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. In the present study, we use transgenic Drosophila melanogaster as a model to analyze in vivo the effect of expressing pseudophosphorylated tau (S199E/T212E/T231E/S262E tau) on pathological human tau (PH-tau) and on the FTDP-17 mutant R406W (PH-tauR406W). We used two different inducers that produced different levels of tau expression. The expression of these forms of tau did not significantly affect the lifespan of the flies. Flies expressing PH-tau displayed a clear locomotor dysfunction compared to those expressing normal tau…regardless of the level of expression. At lower level of expression, this pathological phenotype was found to be age-dependent. At 35 days old, PH-tau flies showed the strongest locomotor impairment compare to flies expressing human tau or control flies (46%, 18% and 18% of flies remained on the bottom of the vials, respectively). At higher levels of expression, PH-tau flies showed these defects at seven days of age and the dysfunction also became significant for flies expressing tauR406W and PH-tauR406W. Whole brain immunochemistry analysis revealed that PH-tau as well as PH-tauR406W appeared to have abnormal mushroom body structures, critical structures involved in olfactory learning and memory in Drosophila. Severe olfactory learning deficits were induced by the expression of PH-tau. Taken together, our findings demonstrate that PH-tau induced a toxic effect in Drosophila, as flies develop both an abnormal motor deficit, associated with disruption of the mushroom body neurons, and impaired olfactory learning.
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Abstract: Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While most of the work described so far focused on the relationship between hyperphosphorylation of tau and microtubule disassembly as well as axonal transport impairments, both phenomena ultimately leading to cell death, little work has been done to study the correlation between tau hyperphosphorylation and DNA damage. As we showed in this study, tau hyperphosphorylation and DNA damage co-occurred under formaldehyde treatment in N2a cells,…indicating that phosphorylated tau (p-Tau) induced by formaldehyde may be involved in DNA impairment. After phosphorylation, the effect of tau in preventing DNA from thermal denaturation was diminished, its ability to accelerate DNA renaturation was lost, and its function in protecting DNA from reactive oxygen species (ROS) attack was impaired. Thus, p-Tau is not only associated with the disassembly of the microtubule system, but also plays a crucial role in DNA impairment. Hyperphosphorylation-mediated dysfunction of tau protein in prevention of DNA structure from damage under the attack of ROS may provide novel insights into the mechanisms underlying tauopathies.
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Abstract: Tauopathies are neurodegenerative diseases characterized behaviorally by dementia and neuropathologically by neurofibrillary tangles and neuronal loss. Tau gene mutations have been found in frontotemporal dementia with parkinsonism linked to chromosome 17, suggesting that mutation of tau induces tauopathy. Studies on in vitro tau aggregation show that tau forms two different intermediate aggregates—called tau oligomers and granular tau oligomers—before forming fibrils. Moreover, studies using a mouse model that expresses human tau demonstrated that the process of neurofibrillary tangle formation, rather than tangles themselves, may cause synapse loss and neuron loss. Further analyses suggest that hyperphosphorylated tau or oligomeric tau is involved…in synaptic loss, whereas granular tau oligomers are responsible for neuronal loss. Thus, different forms of tau aggregates are involved in the different pathological changes that occur in tauopathies.
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Abstract: Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R…human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimer's disease brains that would allow stratification of Alzheimer's disease patients.
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Abstract: Microtubule-based axonal transport is believed to become globally disrupted in Alzheimer's disease in part due to alterations of tau expression or phosphorylation. We previously showed that axonal transport rates along retinal ganglion axons are unaffected by deletion of normal mouse tau or by overexpression of wild-type human tau. Here, we report that htau mice expressing 3-fold higher levels of human tau in the absence of mouse tau also display normal fast and slow transport kinetics despite the presence of abnormally hyperphosphorylated tau in some neurons. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) exhibit normal…distributions along optic axons of these mice. These studies demonstrate that human tau overexpression, even when associated with a limited degree of tau pathology, does not necessarily impair general axonal transport function in vivo.
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Abstract: Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that has been fully studied for its structure, receptor, and signaling pathways and its multiplex effects on neural system, skeletal muscle, and weight control. Recent research demonstrates that CNTF also plays an important role in neurogenesis and the differentiation of neural stem cells. In this article, we summarize the general characteristics of CNTF and its function on neural stem cells, which could be a valuable therapeutic strategy in treating neurological disorders.

Abstract: The work presented herein addresses a specific portion of the tau pathology, pre-fibrillar oligomers, now thought to be important pathological components in Alzheimer's disease and other neurodegenerative tauopathies. In previous work, we generated an antibody against purified recombinant cross-linked tau dimers, called Tau Oligomeric Complex 1 (TOC1). TOC1 recognizes tau oligomers and its immunoreactivity is elevated in Alzheimer's disease brains. In this report, we expand upon the previous study to show that TOC1 selectively labels tau oligomers over monomers or polymers, and that TOC1 is also reactive in other neurodegenerative tauopathies. Using a series of deletion mutants spanning the tau…molecule, we further demonstrate that TOC1 has one continuous epitope located within amino acids 209–224, in the so-called proline rich region. Together with the previous study, our data indicates that TOC1 is a conformation-dependent antibody whose epitope is revealed upon dimerization and oligomerization, but concealed again as polymers form. This characterization of the TOC1 antibody further supports its potential as a powerful biochemical tool that can be used to better investigate the involvement of tau in neurodegenerative diseases.
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Abstract: Member 4 of the sodium/bile acid co-transporter family of proteins (SLC10A4) was discovered as a synaptic vesicle protein. The distribution of Slc10a4 protein in the brain has only so far been assessed in adult rats. Here, we assessed the regional distribution of SLC10A4 in aged human brain by immunohistochemistry. The protein was ubiquitously expressed, particularly in the cholinergic and monoaminergic neurons and in the lateral geniculate body. The protein expression was not influenced by the postmortem delay or fixation time. Synaptic alterations are reported to be seen in Alzheimer's disease (AD) and the suggested function of SLC10A4 as a vesicular…transporter for cholinergic neurotransmitters proposes a link between this protein and AD. With increased severity of AD-related pathology, depletion of SLC10A4 expression was noted in the transentorhinal cortex. Intriguingly, in the most severely affected cases (Braak V), two patterns were noted, i.e., those with severe depletion of SLC10A4 and those with numerous neurons displaying SLC10A4. In conclusion, assessment of the expression of SLC10A4 by means of immunohistochemistry is feasible. The observed depletion of SLC10A4 with increase in the severity of AD-related neuronal degeneration is interesting and the observation that some subjects in Braak V displayed none and some displayed numerous SLC10A4 immunoreactive neurons is intriguing. Assessment of the SLC10A4 protein in neurodegenerative diseases or diseases affecting lateral geniculate body should be carried out to investigate whether alterations in the expression of SLC10A4 in synaptic vesicles might be used as a marker of transmitter deficits (cholinergic, monoaminorgic) or other synaptic pathology.
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Abstract: The relationship between depression and Alzheimer's disease (AD) has always been relevant and controversial. Here, we briefly review epidemiological and biological studies that have investigated these disorders and then introduce our recent research about postmortem brains from patients with major depressive disorder (MDD). Our novel methodological approaches have revealed that MDD may be associated with an unknown type of myelin/myelination abnormalities in the frontopolar cortex. Based mainly on our findings, as well as on neuropathological observations by Braak and Braak (Acta Neuropathol 9, 197-201, 1996), we discuss the possible existence of an as yet unknown common mechanism linking the pathophysiologies…underlying both depression and AD.
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Abstract: The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the…CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
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Abstract: Background/Objective: Type 2 diabetes increases the risk for developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. Methods: Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood,…cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. Results: We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3β, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. Conclusion: Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes.
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